Liposomes, also known as vesicles have been designed to encapsulate a cargo of pharmacological agents useful for in vivo purposes such as the diagnosis and treatment of various diseases and conditions. In addition, particulate matter in the form of therapeutic emulsions used as drug carriers, for example, has been shown to enhance therapeutic indices. These cargo-carrying liposomes and particulate matter have, experimentally, shown potential for being site-specific carrier systems for a variety of such agents. Agents so delivered to designated sites in vivo demonstrate significantly enhanced therapeutic indices. Concurrently, a decrease in unwanted side effects and wasted portions of dosages are achieved. Agents not so couried spread to nonspecific and often undesirable areas of the body, and possibly cause side effects.
The advantages of the prior art in vive carrier system have been offset, however, by the deleterious effects of the body's reticuloendothelial system (the "RES"), mainly the liver and spleen. The RES is the body's defense system, acting to screen the body's circulation. The RES will gradually scavenge from the circulation all material it considers foreign. Liposomes and particulate matter have certain physical characteristics which render them susceptible to removal by the RES. Once recognized, liposomes and particulate matter, whether given or not given a site-specific molecule for site-specific delivery, are quickly phagocytosed by the RES along with their cargo. These prior revolutionary carrier systems have, until the present invention, and the preceding invention of U.S. Pat. No. 4,501,728, remained hampered by the RES.
In said earlier invention, U.S. Pat. No. 4,501,728, the sialic acid mechanism for RES avoidance is a system consisting essentially of a biochemical membrane having sialic acid residues that mask the surface membrane from recognition by the RES cells.
Despite the successful application of sialic acid residues to the liposome carrier system and particulate matter, liposomes so disguised from the RES were nevertheless eventually subject to enzymatic action of endogenous neuraminidase in the blood. Specifically, it was found that neuraminidase eventually cleaves the chemical bond between sialic acid and its attached sugar (galactose), thereby allowing the galactose (sugar) on the surface of the liposome to be recognized by the RES's Ashwell receptor of the liver.
Enzymatic removal of the sialic acid is time-dependent. Liposomes or particulate matter intended to circulate for longer periods of time in the vascular system or until localized to a binding-site, are removed by the RES once the sialic acid mask is compromised or lost.